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J Am Chem Soc. 2012 Apr 11;134(14):6316-25. doi: 10.1021/ja212188r. Epub 2012 Mar 27.

Enhanced epimerization of glycosylated amino acids during solid-phase peptide synthesis.

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  • 1Chemical Biology Laboratory, National Cancer Institute, 376 Boyles Street, Building 376, Frederick, Maryland 21702, USA.

Abstract

Glycopeptides are extremely useful for basic research and clinical applications, but access to structurally defined glycopeptides is limited by the difficulties in synthesizing this class of compounds. In this study, we demonstrate that many common peptide coupling conditions used to prepare O-linked glycopeptides result in substantial amounts of epimerization at the α position. In fact, epimerization resulted in up to 80% of the non-natural epimer, indicating that it can be the major product in some reactions. Through a series of mechanistic studies, we demonstrate that the enhanced epimerization relative to nonglycosylated amino acids is due to a combination of factors, including a faster rate of epimerization, an energetic preference for the unnatural epimer over the natural epimer, and a slower overall rate of peptide coupling. In addition, we demonstrate that use of 2,4,6-trimethylpyridine (TMP) as the base in peptide couplings produces glycopeptides with high efficiency and low epimerization. The information and improved reaction conditions will facilitate the preparation of glycopeptides as therapeutic compounds and vaccine antigens.

PMID:
22390544
PMCID:
PMC3324660
DOI:
10.1021/ja212188r
[PubMed - indexed for MEDLINE]
Free PMC Article
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